This invention relates to a pharmaceutical composition for the treatment of cognitive disorders of cerebrovascular origin, which comprises idebenone in synergistic combination with nimodipine.
Cerebrovascular disease has three etiopathogenesies that cause brain injury. The etiology of cardiac embolism has a well-defined treatment using anticoagulant agents. The typical treatment for obstructive etiology of main arteries, carotid and vertebral, is surgery and use of platelet anti-aggregant agents. The third etiology is the disease of small brain penetrating arteries. The pathogenesis of sick arterioles is a fibrohyaline, lipohyaline, amyloid or eosinophil deposit and thickening. In cases of abnormally small brain arterioles there exists controversy as regards treatment, and for secondary prophylaxis of new episodes, platelet anti-aggregants are also used.
Mild to moderate cognitive cerebrovascular disease is generally manifested through an impairment in attention and memory, behavioral and relation disorders, abulia, lack of interest and poor personal care.
A branch of clinical-neurological research is based on the concept of neuroprotection, providing the brain tissue with an optimized metabolism that may tolerate an intermediate state of injury, so that if a reduction in blood flow to the brain, ranging from 30 to 20 ml/100 g of tissue/minute, causes an ischaemic injury to the cells, it will remain potentially reversible.
Idebenone is a benzoquinone which pharmacodynamic properties have been established in the line of drugs with cytoprotecting effects, as described in U.S. Pat. No. 4,271,083. Idebenone is the general name of 6-(10-hydroxydecil)-2,3-dimethoxy-5-methyl-1,4-benzoquinone compound. Data from in vitro essays (mitochondrial preparations of rat and dog brain) suggest that the cytoprotecting action of idebenone is achieved by facilitating the conveyance of electrons in the mitochondrial respiratory cycle, inhibiting lipid peroxidation, reducing non-breathing oxygen consumption and stimulating ATP formation.
Effects on memory and learning capabilities have been tested on animals, attenuating the abnormal amnesic and learning behavior as induced by brain ischemia.
Idebenone is widely delivered to different tissues, including the brain, and is detected in eleven different regions of the brain.
Oral administration of idebenone to healthy. volunteers, either in an single dose or in multiple doses of 45 or 100 mg, reaches a maximum concentration in plasma in an average period of 1 to 2 hours. Accumulation does not occur after repeated doses.
Therapeutic potential of this substance is in cognitive deterioration, especially in those patients having vascular problems that tend to worsen.
Nimodipine is a non-symmetrical dihydropyridine in respect of ester groups of positions 3- and 5-, as disclosed in U.S. Pat. No. 3,799,934, wherein it is described as a coronary vasodilator agent having anti-hypertension properties, as well. Nimodipine is the general name for the 1,4-dyhidro-5-(isopropoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridine-carboxylate of 2-methoxyethyl compound. In U.S. Pat. No. 4,406,906 the use of nimodipine for the treatment of brain insufficiencies is disclosed, in particular those related to insufficiencies in brain vascular circulation. Further studies and researches disclose that nimodipine, as a lipophilic ester, crosses the blood-brain barrier. The preferred action site of the drug is over the brain flow and calcium cell homeostasis. One hypothesis about pharmacological action relates to regulation of cell membrane mechanisms that preserve appropriate calcium concentration. The failure of these systems results in an elevation of intracell calcium, which is considered as cytotoxic, causing an activation of calcium-dependent proteases and perturbations of cell cytoskeleton. Such situations related to calcium displacement have been assessed in basic tests on smooth muscle cell isolated from the vessels.
Several studies have been performed on human beings in order to measure the effects of nimodipine action on patients with brain ischemia. Results of some of them show an improvement in the cognitive functioning in sick people with vascular dementia.
Surprisingly, the present inventors have found that the joint administration of nimodipine and idebenone provides a therapeutic effect that is superior to that provided by each compound alone.
Therefore, this invention provides a new pharmaceutical composition for the prophylaxis and treatment of cognitive cerebrovascular disease which includes synergistically effective amounts of idebenone in combination with nimodipine.
It is a further object of the invention to provide a method for the prophylaxis or treatment of cognitive cerebrovascular disease in a mammal, which comprises the administration to a mammal of an effective amount of idebenone in combination with nimodipine.
It is still another object of the invention to use idebenone in combination with nimodipine for the preparation of a pharmaceutical composition for the prophylaxis or treatment of cognitive cerebrovascular disease.
Other features, advantages and embodiments of the invention will be apparent for those skilled in the art from the description below, the accompanying examples and appended claims.
The pharmaceutical composition of the present invention can be orally administered in the form of doses prepared from the admixture of each of the active compounds of idebenone and nimodipine with a pharmaceutically acceptable carrier or excipient.
It should be understood that the use of pharmaceutically acceptable nimodipine salts are also within the scope of the present invention.
The pharmaceutical composition of the present invention can be furnished in alternative dosage forms according to the processes as follows: (i) active compounds are optionally admixed with pharmaceutically acceptable excipients, by any pharmaceutical technique already known, so as to provide a dosage form; (ii) active compounds are processed separately with pharmaceutically acceptable excipients, for further combination in a dosage form; or (iii) compounds are processed separately with pharmaceutically acceptable excipients, for providing independent dosage forms which shall be administered as a set.
Preferably, the pharmaceutical composition of the invention is provided as an oral administration form which comprises the combination of idebenone and nimodipine. Oral administration forms can be tablets, lozenges, capsules, granules, and the like.
The pharmaceutical composition of this invention can be prepared by those known processes using excipients such as binders, disintegrants, lubricants, tablet glidants, tablet opaquants, colorants and other additives which use is known in the art.
Exemplary excipients are sucrose, lactose, glucose, starch, mannitol, sorbitol, cellulose, talc, and cyclodextrins.
As used in the present invention, xe2x80x9ctablet bindersxe2x80x9d mean any substance that cause adhesion of powder particles in the granulation of a tablet. Such compounds are exemplified by, but not limited to, gum arabic, alginic acid, tragacanth, sodium carboxy-methylcellulose, (poly)vinylpirrolidone); compressible sugar (e.g., NuTab), ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone, pregelatinized starch, polyethylene glycol, sucrose, starch, collagen, albumin, polyethylene oxide, mycrocristalline cellulose and combinations thereof, as well as other materials that are well known to those of ordinary skill in the art.
As used in the present invention, the term xe2x80x9ctablet disintegrantsxe2x80x9d means those compounds used in solid dosage forms, to promote disintegration of the solid mass in smaller particles which are more easily dispersed or dissolved. Such compounds include by way of example and without limitation, starch, such as corn starch, potato starch, pregelatinized and modified starches, sweeteners, clays such as bentonite, microcrystaline cellulose (e.g., Avicel), calcium carboxymethylcellulose, potassium polyacriline cellulose (e.g., Amberlite), alginates, sodium starch glycolate, gums such as agar, guar gum, locust bean, pectin, tragacanth, and combinations thereof, as well as other materials that are well known to those of ordinary skill in the art.
As used in the present invention, the term xe2x80x9ctablet lubricantsxe2x80x9d means substances used in the formulation for reducing friction during tablet compression. Such compounds include by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, and combinations thereof, as well as other materials that are well known to those of ordinary skill in the art.
As used in the present invention, the term xe2x80x9ctablet glidantsxe2x80x9d means those agents used in tablet and capsule formulation for improving granulation fluidity. Such compounds include by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silica hydrogel, corn starch, talc and combinations thereof, as well as other materials that are well known to those of ordinary skill in the art.
As used in the present invention, the term xe2x80x9ctablet or capsule opaquantxe2x80x9d means those compounds used for achieving an opaque coating over the tablets or capsules to provide an opacity that can help in photostabilization in the case of photosensitive agents. Such compounds include by way of example and without limitation, titanium dioxide, and other materials that are well known to those of ordinary skill in the art.
Whenever necessary, the composition can be provided in a sustained release dosage form.
Preferred dosage forms are those having 10 to 1000 mg of idebenone and 6 to 600 mg of nimodipine.
Certainly, administered dosage should be carefully determined according to age, weight and condition of the person being treated, and also according to administration form, and dosage form and regime. Satisfactory results can be obtained through oral administration of 0.15 to 15 mg of ibedenone/kilogram of body weight/day in combination with 0.1 to 10 mg of nimodipine/kilogram of body weight/day. An adequate dosage for prophylaxis or treatment of mild to moderate cerebrovascular disease should comprise about 90 mg/day of idebenone in combination with 60 mg/day of nimodipine. Preferably, two daily doses, orally administered, of a dosage form having 45 mg of idebenone and 30 mg of nimodipine will provide satisfactory results.
The composition of the invention can be used in the treatment of symptoms associated to mild to moderate cerebrovascular disorders, such as memory and attention alterations, behavioral and relation disorders, deficit in personal care, and the like.
As explained below, the synergistic action of the combination of ibedenone and nimodipine produces therapeutic effects superior to those provided by each drug separately, combining synergistically their respective effects, such as: activation of metabolism, increasing ATP production, replacement of neuronal energetic reserve, capture of free radicals, reestablishing of neurotransmitting process, selective blockade of calcium channels in arteries and neuron protection of neurovascular structure, prophylaxis of neurological deficit due to cerebrovascular insufficiency.
The following formulation and examples are included in order to better illustrate the invention, but these examples shall not be considered a limitation to the invention, the scope of which is established in the appended claims.